TCF-1 controls T_reg cell functions that regulate inflammation, CD8⁺ T cell cytotoxicity and severity of colon cancer

The transcription factor TCF-1 is essential for the development and function of regulatory T (T_reg) cells; however, its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-sequencing analysis identified effector memory T cells and central memory T_reg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core T_reg cell transcriptional signature, but promoted alternative signaling pathways whereby T_reg cells became activated and gained gut-homing properties and characteristics of the T_H17 subset of helper T cells. TCF-1-deficient T_reg cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4⁺ T cell polarization and inflammation. In mice with polyposis, T_reg cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating T_reg cells of patients with colorectal cancer showed lower TCF-1 expression and increased T_H17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, T_reg cell-specific TCF-1 expression differentially regulates T_H17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.